The Peptide Repertoires of HLA-B27 Subtypes Differentially Associated to Spondyloarthropathy (B*2704 and B*2706) Differ by Specific Changes at Three Anchor Positions

Sesma, Laura; Montserrat, Verónica; Lamas, José Ramón; Marina, Anabel; Vázquez, Jesús; Castro, José A. Łópez de

doi:10.1074/jbc.m200371200

Cited by 61 publications

(61 citation statements)

References 44 publications

(41 reference statements)

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“…This view was challenged by the finding that the AS-associated subtype B*2707 failed to show a C-terminal Tyr motif upon pool sequencing (32). Failure to bind peptides with C-terminal Tyr was recently confirmed for B*2706 (33) and, in the present study, for B*2709, but several novel aspects were revealed by our results now. First, although B*2709 specificity is highly restricted to peptides with C-terminal aliphatic or Phe residues two peptides with C-terminal Arg and Tyr, respectively, were found in the B*2709-bound peptide pool.…”

Section: Discussioncontrasting

confidence: 48%

Differential Association of HLA-B2705 and B2709 to Ankylosing Spondylitis Correlates with Limited Peptide Subsets but Not with Altered Cell Surface Stability

Ramos

Paradela

Vázquez³

et al. 2002

Journal of Biological Chemistry

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In contrast to HLA-B*2705, B*2709 is weakly or not associated to ankylosing spondylitis. Both allotypes differ by a single D116H change. We compared the B*2705-and B*2709-bound peptide repertoires by mass spectrometry to quantify the effect of B*2709 polymorphism on peptide specificity. In addition, shared and differentially bound ligands were sequenced to define the structural features of the various peptide subsets. B*2705 shared 79% of its peptide repertoire with B*2709. Shared ligands accounted for 88% of the B*2709-bound repertoire. All B*2705 ligands not bound to B*2709 had Cterminal basic or Tyr residues. Most B*2709-bound peptides had C-terminal aliphatic and Phe residues, but two showed C-terminal Arg or Tyr. The B*2709-bound repertoire included 12% of peptides not found in B*2705. These had aliphatic C-terminal residues, which are also favored in B*2705. However, these peptides bound weakly B*2705 in vitro, indicating distinct contribution of secondary anchor residues in both subtypes. Differences in peptide binding did not affect the ratio of native to ␤ 2 -microglobulin-free HLA-B27 heavy chain at the cell surface. Our results suggest that weaker association of B*2709 with ankylosing spondylitis is based on differential binding of a limited subset of natural ligands by this allotype.

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Section: Discussioncontrasting

confidence: 48%

Differential Association of HLA-B2705 and B2709 to Ankylosing Spondylitis Correlates with Limited Peptide Subsets but Not with Altered Cell Surface Stability

Ramos

Paradela

Vázquez³

et al. 2002

Journal of Biological Chemistry

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111

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“…HLA-B27 subtypes bind distinct but overlapping peptide repertoires, a feature that correlates with differential association of the subtypes with AS (16,26,27). However, since the identification of putative arthritogenic peptides remains elusive and the role of CD8 T cells in B27-associated disease in transgenic rats has been questioned (42), other alternatives must be considered.…”

Section: Discussionmentioning

confidence: 99%

“…So far, the antigen-presenting specificity is the only known feature of B27 to show such a correlation, since subtypes differentially associated with AS bind to distinct peptide subsets (25)(26)(27)(28).…”

mentioning

confidence: 99%

Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

Vázquez

Castro

2005

Arthritis & Rheumatism

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Objective. To determine whether the cell surface features of HLA-B27 subtypes reported to be differentially associated with ankylosing spondylitis (AS) differ in a way that correlates with disease susceptibility.Methods. Human cell transfectants expressing or lacking the transporter associated with antigen processing were used to determine the cell surface expression of B27 subtypes by flow cytometry with antibodies recognizing the B27 heterodimer or ␤ 2 -microglobulin (␤ 2 m)-free heavy chains.Results. In lymphoid cells with an intact peptideloading complex, all B27 subtypes, irrespective of their association with disease, showed similar ratios of free heavy chain to heterodimer, suggesting similar surface stability. A substantial decrease in dissociated heavy chains, which never reached 100%, was observed upon addition of a B27 ligand, with no significant differences among subtypes. This is compatible with similar surface expression of irreversible ␤ 2 m-free heavy chain forms among subtypes differentially associated with disease. In cells lacking the transporter associated with antigen processing, both disease-associated and non-diseaseassociated subtypes expressed a population of heterodimers at 26°C that was less stable than the population expressed at 37°C. In the presence of exogenous peptide, the expression of heterodimers increased, without a concomitant decrease in ␤ 2 m-free heavy chains. This suggests that in these cells, and for all subtypes tested, most of the dissociated heavy chains at the cell surface are in irreversible forms. At 37°C, the expression of ␤ 2 m-free B27 heavy chains was very low on T2 transfectant cells. Conclusion. HLA-B27 subtypes showing differential associations with AS are similar in their extent of ␤ 2 m dissociation and surface expression of free heavy chains.Class I major histocompatibility complex (MHC) proteins are heterodimers consisting of a polymorphic heavy chain that is noncovalently bound to ␤ 2 -microglobulin (␤ 2 m), a nonpolymorphic polypeptide. Assembly of MHC molecules takes place in the endoplasmic reticulum (ER), where they constitutively bind peptides. These arise mainly from proteasomal degradation in the cytosol, are transported into the lumen of the ER by means of the transporter associated with antigen processing (TAP), and bind, sometimes after trimming, to the class I molecule in a process involving several proteins collectively known as the peptide-loading complex (1). Peptides bound with sufficient affinity stabilize the native conformation of the nascent class I molecule. When this happens, the peptide-MHC complex is released from the ER and traffics to the cell surface. In cells lacking TAP, the peptide supply into the ER and the expression of class I MHC are drastically reduced. However, at 26°C, MHC molecules that are presumably devoid of peptide can be sufficiently stable to leave the ER and reach the cell surface (2).The ␤ 2 m-free class I MHC polypeptides are found at the cell surface. This can be revealed, for example, by cell surface stain...

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“…In particular, the effect of the changes at residue 116 in the two subtypes not associated with AS -B*2706 and B*2709 -which results in a drastic restriction of C-terminal peptide motifs [19,20], is now clearly understood. Second, a better basis is provided to address the molecular mimicry between self and foreign HLA-B27 ligands, an issue that might be of outstanding relevance in the pathogenesis of spondyloarthropathies [4].…”

Section: Resultsmentioning

confidence: 99%

“…These interactions are little affected by changes at residue 116 [18], so that peptides with aliphatic P residues are largely shared between HLA-B27 subtypes differentially associated with AS [19,20].…”

Section: Hla-b27 In Healthmentioning

confidence: 99%

HLA‐B27: portraying immunodominant viral epitopes

Castro

2005

Eur J Immunol

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Although the crystal structure of HLA-B27 has been known for a long time, only recently have X-ray diffraction studies of this molecule in complex with individual peptides become available. The report of three such structures involving viral epitopes that are immunodominant in HLA-B27-restricted T cell responses against influenza, EpsteinBarr and HIV viruses significantly improves our perception of critical aspects of the immunological and pathogenetic roles of HLA-B27, including (1) the molecular basis of its peptide-binding specificity and how this is modulated by subtype polymorphism, (2) the relationship between the structural and the antigenic features of immunodominant viral epitopes, (3) the basis for long term non-progression to AIDS of HIV-infected HLA-B27 + individuals, and (4) the structural features of microbial peptides influencing NK receptor engagement. Here, I discuss the implications of this and related studies for the relevance of HLA-B27 in host defense and as a pathogenetic molecule in spondyloarthritis.

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The Peptide Repertoires of HLA-B27 Subtypes Differentially Associated to Spondyloarthropathy (B2704 and B2706) Differ by Specific Changes at Three Anchor Positions

Cited by 61 publications

References 44 publications

Differential Association of HLA-B2705 and B2709 to Ankylosing Spondylitis Correlates with Limited Peptide Subsets but Not with Altered Cell Surface Stability

Differential Association of HLA-B2705 and B2709 to Ankylosing Spondylitis Correlates with Limited Peptide Subsets but Not with Altered Cell Surface Stability

Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

HLA‐B27: portraying immunodominant viral epitopes

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The Peptide Repertoires of HLA-B27 Subtypes Differentially Associated to Spondyloarthropathy (B*2704 and B*2706) Differ by Specific Changes at Three Anchor Positions

Cited by 61 publications

References 44 publications

Differential Association of HLA-B*2705 and B*2709 to Ankylosing Spondylitis Correlates with Limited Peptide Subsets but Not with Altered Cell Surface Stability

Differential Association of HLA-B*2705 and B*2709 to Ankylosing Spondylitis Correlates with Limited Peptide Subsets but Not with Altered Cell Surface Stability

Similar cell surface expression of β2‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

HLA‐B27: portraying immunodominant viral epitopes

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The Peptide Repertoires of HLA-B27 Subtypes Differentially Associated to Spondyloarthropathy (B2704 and B2706) Differ by Specific Changes at Three Anchor Positions

Differential Association of HLA-B2705 and B2709 to Ankylosing Spondylitis Correlates with Limited Peptide Subsets but Not with Altered Cell Surface Stability

Differential Association of HLA-B2705 and B2709 to Ankylosing Spondylitis Correlates with Limited Peptide Subsets but Not with Altered Cell Surface Stability

Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis